MGMT gene silencing and benefit from temozolomide in glioblastoma.

BACKGROUND: Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. METHODS: We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. RESULTS: The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. CONCLUSIONS: Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit

Requirements and limitations of imaging airway smooth muscle throughout the lung in vivo

Clinical visualization and quantification of the amount and distribution of airway smooth muscle (ASM) in the lungs of individuals with asthma has major implications for our understanding of airway wall remodeling as well as treatments targeted at the ASM. This paper theoretically investigates the feasibility of quantifying airway wall thickness (focusing on the ASM) throughout the lung in vivo by means of bronchoscopic polarization-sensitive optical coherence tomography (PS-OCT). Using extensive human biobank data from subjects with and without asthma in conjunction with a mathematical model of airway compliance, we define constraints that airways of various sizes pose to any endoscopic imaging technique and how this is impacted by physiologically relevant processes such as constriction, inflation and deflation. We identify critical PS-OCT system parameters and pinpoint parts of the airway tree that are conducive to successful quantification of ASM. We further quantify the impact of breathing and ASM contraction on the measurement error and recommend strategies for standardization and normalization.Michael J. Hackmann, John G. Elliot, Francis H.Y. Green, Alvenia Cairncross, Barry Cense, Robert A. McLaughlin, David Langton, Alan L. James, Peter B. Noble, Graham M. Donova

cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant

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cIMPACT-NOW update 1: Not Otherwise Specified (NOS) and Not Elsewhere Classified (NEC)

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